A majority of available treatment options for metachromatic leukodystrophy (MLD) rely on relieving symptoms. However, the recent approval of Lenmeldy (atidarsagene autotemcel) is the first ever FDA-approved gene therapy option for the disease.

According to a news release from the U.S. Food and Drug Administration (FDA), Lenmeldy’s approval came on Monday, March 19, 2024. Lenmeldy is a single dose autologous hematopoietic stem cell-based gene therapy. This treatment is personalized to each individual and created from each individual’s hematopoietic stem cells. Once removed from the body, these cells are genetically modified to have functional ARSA copies (this is the gene that is mutated in MLD). Once the cells are transplanted back into the body, the modified stem cells spread, producing the arylsulfatase A (ARSA) enzyme and clearing fatty subtances from cells.

Doctors and researchers believe that Lenmeldy could stop disease progression in children with:

• Pre-symptomatic late-infantile MLD. This means that infants have MLD but have yet to show symptoms.
• Either pre-symptomatic or early symptomatic early juvenile MLD. These children are slightly older. They either have no symptoms or have early symptoms.

Lenmeldy’s approval hinged, in part, on clinical data which included 37 children with metachromatic leukodystrophy. When compared to a natural history study, researchers found that:

• Every child with pre-symptomatic late infantile metachromatic leukodystrophy that was treated with Lenmeldy lived to six years old. Only 58% of those who remained untreated reached the same endpoint.
• By age five, children receiving Lenmeldy experienced improvements in gait. Additionally, a large majority showed normal language and cognition.
• When compared to the natural history cohort, researchers found that Lenmeldy reduced mortality risk.
• Lenmeldy was relatively safe and well-tolerated, though some adverse reactions did occur. These included liver enlargement, fever, neutropenia (low white blood cell count), rashes, and respiratory, medical line, viral, and gastrointestinal infections.

Understanding Metachromatic Leukodystrophy (MLD)

While ARSA mutations are the most common cause of metachromatic leukodystrophy, a rare hereditary disease, this condition may also result from PSAP gene mutations. These mutations cause an enzyme deficiency. Normally, this enzyme breaks down fats that contain sulfatides. When this enzyme is deficient, these fats and sulfatides build up, leading to destruction of the myelin sheath. The myelin sheath is the protective covering of nerve cells. In MLD, the myelin sheath is damaged in both the central and peripheral nervous systems. An estimated 1 in every 40,000 – 160,000 people have metachromatic leukodystrophy.

As you might’ve noticed above, MLD is usually broken into three subtypes: late-infantile, juvenile, and adult. Late-infantile MLD is the most common form, comprising around 50% of MLD cases. Children with this form often experience speech and language loss, muscle weakness, and difficulty walking. Unfortunately, many children with this form do not survive past childhood. 20-30% of people have the juvenile form, where symptoms may include behavioral problems and difficulty completing schoolwork. Finally, the adult form comprises 15-20% of cases. Symptoms appear in teenage years or later and may manifest as difficulties with school or work, alcohol or drug abuse, delusions, vision loss, or hallucinations.